Asthma is a complex disease involving the concerted actions of multiple inflammatory and immune cells, spasmogens, inflammatory mediators, cytokines and growth factors. In recent practice there have been four major classes of compounds used in the treatment of asthma, namely bronchodilators (e.g., xcex2-adrenoceptor agonists), anti-inflammatory agents (e.g., corticosteroids), prophylactic anti-allergic agents (e.g., cromolyn sodium) and xanthines (e.g., theophylline) which appear to possess both bronchodilating and anti-inflammatory activity.
Theophylline has been a preferred drug of first choice in the treatment of asthma. Although it has been touted for its direct bronchodilatory action, theophylline""s therapeutic value is now believed to also stem from anti-inflammatory activity. Its mechanism of action remains unclear. However, it is believed that several of its cellular activities are important in its activity as an anti-asthmatic, including cyclic nucleotide phosphodiesterase inhibition, adenosine receptor antagonism, stimulation of catecholamine release, and its ability to increase the number and activity of suppressor T-lymphocytes. While all of these may actually contribute to its activity, only PDE inhibition may account for both the anti-inflammatory and bronchodilatory components. However, theophylline is known to have a narrow therapeutic index and a wide range of untoward side effects which arc considered problematic.
Of the activities mentioned above, theophylline""s activity in inhibiting cyclic nucleotide phosphodiesterase has received considerable attention recently. Cyclic nucleotide phosphodiesterases (PDEs) have received considerable attention as molecular targets for anti-asthmatic agents. Cyclic 3xe2x80x2,5xe2x80x2-adenosine monophosphate (cAMP) and cyclic 3xe2x80x2,5xe2x80x2-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids. At least two therapeutically important effects could result from phosphodiesterase inhibition, and the consequent rise in intracellular adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) or guanosine 3xe2x80x2,5xe2x80x2-monophosphate (CGMP) in key cells in the pathophysiology of asthma. These are smooth muscle relaxation (resulting in bronchodilation) and anti-inflammatory activity.
It has become known that there are multiple, distinct PDE isoenzymes which differ in their cellular distribution. A variety of inhibitors possessing a marked degree of selectivity for one isoenzyme or the other have been synthesized.
The structure-activity relationships (SAR) of isozyme-selective inhibitors has been discussed in detail, e.g., in the article of Theodore J. Torphy, et al., xe2x80x9cNovel Phosphodiesterase Inhibitors For The Therapy Of Asthmaxe2x80x9d, Drug News and Prospectives, 6(4) May 1993, pages 203-214. The PDE enzymes can be grouped into five families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. PDE I is stimulated by Ca2+/calmodulin. PDE II is cGMP-stimulated, and is found in the heart and adrenals. PDE III is cGMP-inhibited, and inhibition of this enzyme creates positive inotropic activity. PDE IV is cAMP specific, and its inhibition causes airway relaxation, antiinflammatory and antidepressant activity. PDE V appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE V inhibitors may have cardiovascular activity.
While there are compounds derived from numerous structure activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited. Analogues of rolipram, which has the following structural formula (A): 
and of RO-20-1724, which has the following structural formula (B): 
have been studied.
U.S. Pat. No. 4,308,278 discloses compounds of the formula (C) 
wherein R1 is (C3-C6)cycloalkyl or benzyl; each of R2 and R3 is hydrogen or (C1-C4)alkyl; R4 is R2 or alkoxycarbonyl; and R5 is hydrogen or alkoxycarbonyl.
Compounds of Formula (D) are disclosed in U.S. Pat. No. 3,636,039. These compounds are benzylimidazolidinones which act as hypertensive agents. 
Substituents R1-R4 in Formula D represent a variety of groups, including hydrogen and lower alkyl.
PCT publication WO 87/06576 discloses antidepressants of Formula E: 
wherein R1 is a polycycloalkyl group having from 7 to 11 carbon atoms R2 is methyl or ethyl; X is O or NH; and Y comprises a mono- or bicyclic heterocyclic group with optional substituents.
Rolipram, which was initially studied because of its activity as an anti-depressant, has been shown to selectively inhibit the PDE IV enzyme and this compound has since become a standard agent in the classification of PDE enzyme subtypes. There appears to be considerable therapeutic potential for PDE IV inhibitors. Early work focused on depression as a CNS therapeutic endpoint and on inflammation, and has subsequently been extended to include related diseases such as dementia and asthma. In-vitro, rolipram, RO20-1724 and other PDE IV inhibitors have been shown to inhibit (1) mediator synthesis/release in mast cells, basophils, monocytes and eosinophils; (2) respiratory burst, chemotaxis and degranulation in neutrophils and eosinophils; and (3) mitogen-dependent growth and differentiation in lymphocytes (The PDE IV Family Of Calcium-Phosphodiesterases Enzymes, John A. Lowe, III, et al., Drugs of the Future 1992, 17(9):799-807).
PDE IV is present in all the major inflammatory cells in asthma including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down regulation of inflammatory cell activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. These are undesirable side effects for an anti-inflammatory agent. Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation. With this well-known distinction between PDE isozymes, the opportunity for concomitant anti-inflammation and bronchodilation without many of the side effects associated with theophylline therapy is apparent. The increased incidence of morbidity and mortality due to asthma in many Western countries over the last decade has focused the clinical emphasis on the inflammatory nature of this disease and the benefit of inhaled steroids. Development of an agent that possesses both bronchodilatory and antiinflammatory properties would be most advantageous.
It appears that selective PDE IV inhibitors should be more effective with fewer side effects than theophylline. Clinical support has been shown for this hypothesis. Furthermore, it would be desirable to provide PDE IV inhibitors which are more potent and selective than rolipram and therefore have a lower IC50 so as to reduce the amount of the agent required to effect PDE IV inhibition.
In recent years, several different compounds have been suggested as possible therapeutic compositions which achieve the desired PDE IV inhibition without the side effects alluded to above. However, these efforts have been chiefly directed to developing non-specific derivatives of particular classes of compounds, i.e. rolipram analogs, benzoxazoles, adenines, thioxanthines, etc. These efforts, however, have resulted in a myriad of compounds having a wide range of PDE IV IC50""s. Often, the general formulas disclosed yield several compounds which have poor levels of PDE IV inhibition and/or lack sufficient specificity. Consequently, these efforts often provide no assurance that any particular derivative within the formula will have the desired combination of high PDE IV inhibition and selectivity.
It is accordingly an object of the present invention to provide new compounds which are more effective selective PDE IV inhibitors than known prior art compounds.
It is another object of the present invention to provide new compounds which act as effective PDE IV inhibitors with lower PDE III inhibition.
It is another object of the present invention to provide methods for treating a patient requiring PDE IV inhibition.
It is another object of the present invention to provide new compounds for treating disease states associated with abnormally high physiological levels of inflammatory cytokines, including tumor necrosis factor.
It is another object of the present invention to provide a method of synthesizing the new compounds of this invention.
It is another object of the present invention to provide a method for treating a patient suffering from disease states such as asthma; allergies; inflammation; depression, dementia, including Alzheimer""s disease, vascular dementia, and multi-in-farct dementia; a disease caused by Human Immunodeficiency Virus; and disease states associated with abnormally high physiological levels of inflammatory cytokines.
Other objects and advantages of the present invention will become apparent from the following detailed description thereof With the above and other objects in view, the present invention comprises compounds having the general formula (I): 
wherein
R3 is selected from the group consisting of
hydrogen;
C1-10alkyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H, xe2x95x90O or benzyloxy, said benzyloxy optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy;
C2-10alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-10cycloalkyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-10cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O
C3-12cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
aryl which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONR2, phenyl or benzyl
ar(C1-4)alkyl wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10alkylcarboxy, halogen, hydroxy, hydroxy(C1-10)alkoxy, nitro, trihalocarbon, benzyloxy, heterocyclyl, C1-10cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy or C3-12cycloalkoxy said alkoxy and cycloalkoxy optionally substituted in one position at the alkyl moiety with hydroxy and said heterocyclyl is optionally substituted with C1-10alkyl; and wherein the alkyl moiety of said ar (C1-4)alkyl is optionally substituted with OH, halogen, C1-10alkoxy and C3-12cycloalkoxy said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl;
heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl, and wherein said alkyl moiety is optionally substituted with OH, C1-10alkoxy, C3-12cycloalkoxy, C3-12cycloalkyl, halogen or halo(C1-10)alkyl;
heteroaryl, which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, CF3, C1-10alkoxy, C3-12cycloalkoxy or oxo; and
heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, trihalocarbon, C1-10alkoxy or C3-12cycloalkoxy;
R8 is selected from the group consisting of
hydrogen;
C1-10alkyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H, xe2x95x90O or benzyloxy, said benzyloxy optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy;
C2-10alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-10cycloalkyl which is optionally substituted with 1-3 substituents chosen from the group. consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-10cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-12cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
aryl which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl;
ar(C1-4)alkyl wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10alkylcarboxy, halogen, hydroxy, hydroxy(C1-10)alkoxy, nitro, trihalocarbon, benzyloxy, heterocyclyl, C1-10cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy or C3-12cycloalkoxy said alkoxy and cycloalkoxy optionally substituted in one position at the alkyl moiety with hydroxy and said heterocyclyl is optionally substituted with C1-10alkyl and wherein the alkyl moiety of said ar (C1-4)alkyl is optionally substituted with OH, halogen, C1-10alkoxy and C3-12cycloalkoxy said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl;
heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl, and wherein said alkyl moiety is optionally substituted with OH, C1-10alkoxy, C3-12cycloalkoxy, C3-12cycloalkyl, halogen or halo(C1-10)alkyl;
heteroaryl, which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, CF3, C1-10alkoxy, C3-12cycloalkoxy or oxo; and
heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, trihalocarbon, C1-10alkoxy or C3-12cycloalkoxy;
R6a and R6b are independently selected from the group consisting of
hydrogen;
C1-10alkyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H, xe2x95x90O or benzyloxy, said benzyloxy optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy,
C2-10alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-10cycloalkyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
C3-10cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, NOCONH2, CO2H or xe2x95x90O;
C3-12cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O;
aryl which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl;
ar(C1-4)alkyl wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10alkylcarboxy, halogen, hydroxy, hydroxy(C1-10)alkoxy, nitro, trihalocarbon, benzyloxy, heterocyclyl, C1-10cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy or C3-12cycloalkoxy said alkoxy and cycloalkoxy optionally substituted in one position at the alkyl moiety with hydroxy and said heterocyclyl is optionally substituted with C1-10alkyl; and wherein the alkyl moiety of said ar (C1-4)alkyl is optionally substituted with OH, halogen, C1-10alkoxy and C3-12cycloalkoxy said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl;
heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl and wherein said alkyl moiety is optionally substituted with OH, C1-10alkoxy, C3-12cycloalkoxy, C3-12cycloalkyl, halogen or halo(C1-10)alkyl;
heteroaryl, which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, CF3, C1-10alkoxy, C3-12cycloalkoxy or oxo; and
heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, trihalocarbon, C1-10alkoxy or C3-12cycloalkoxy;
provided that when R3 is an unsubstituted benzyl group, R6a is a methyl or isopropyl group and R6b is a hydrogen atom;
when R3, R6a and R6b are methyl groups, then R8 is other than a hydrogen atom;
when R8 is methyl or a hydrogen atom, R3 is nether methyl or hydrogen;
when R8 is phenyl, R3 is not methyl;
when R8 is pyridyl, R3 is not a hydrogen atom; and
when R6a and R6b are both hydrogen, then R8 is not hydrogen or alkylC(O)OH;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, R3 is an ar(C1-4)alkyl, wherein the aryl moiety is optionally substituted at 1-3 positions with halogen, nitro, alkoxy, cycloalkoxy or CF3, and wherein the alkyl moiety is optionally substituted with OH, halogen, alkoxy and cycloalkoxy. The aralkyl may be a benzyl, which may be optionally substituted as described above. In other preferred embodiments, the aralkyl is a benzyl substituted with alkoxy and cycloalkoxy.
In other preferred embodiments, R6a is a hydrogen. In other preferred embodiments, R6a is hydrogen and R6b is selected from the group consisting of C1-10alkyl, preferably C1-8alkyl, which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C2-10alkenyl which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C3-10cycloalkyl, preferably C3-8cycloalkyl, which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C3-10cycloalkenyl which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; aryl which is optionally substituted with C1-8alkyl, OH, halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl, amido, C1-8alkylamido, C1-3dialkylamido, C1-8acylamino, C1-8alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl; aralkyl C1-4 wherein the aryl moiety is optionally substituted with halogen, nitro, alkoxy, cycloalkoxy or CF3, and wherein the alkyl moiety is optionally substituted with OH, halogen, alkoxy and cycloalkoxy; heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with C1-8alkyl, OH, halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl, amido, C1-8alkylamido, C1-3dialkylamido, C1-8acylamino, C1-8alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl; and heterocyclylalkyl (C1-C4) wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with C1-8alkyl, OH, halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl, amido, C1-8alkylamido, C1-3dialkylamido, C1-8acylamino, C1-8alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl, and wherein said alkyl moiety is optionally substituted with OH, alkoxy, cycloalkoxy, halogen or haloalkyl; heteroaryl, which is optionally substituted with C1-4alkyl, halogen, nitro, CF3, alkoxy or cycloalkoxy; and heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with C1-4alkyl, halogen, nitro, CF3, alkoxy or cycloalkoxy;
In other preferred embodiments, R6a is hydrogen and R6b is selected from the group consisting of C1-10alkyl, preferably C1-8alkyl, which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C2-10alkenyl which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C3-10cycloalkyl, preferably C3-8cycloalkyl, which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; and C3-10cycloalkenyl, which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O. In particular, R6a may be a hydrogen and R6b may be a C1-8alkyl which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O. In other preferred embodiments of the invention, R6b, N, and R6a form a 3 to 8 membered ring containing at least one carbon atom, from one to three nitrogen atoms, from zero to two oxygen atoms, and from zero to two sulfur atoms, optionally substituted with hydroxy, alkoxy, cycloalkoxy, C1-4alkyl, CO2H, CONH2, xe2x95x90NOH, xe2x95x90NOCONH2, xe2x95x90O.
In other preferred embodiments, R8 is selected from the group consisting of C1-10alkyl, preferably C1-8alkyl, which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C2-10alkenyl, which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C3-10cycloalkyl, preferably C3-8cycloalkyl, which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C3-10cycloalkenyl, which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; C4-8cycloalkylalkyl wherein the cycloalkyl portion is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; aryl which is optionally substituted with C1-8alkyl, OH, halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl, amido, C1-8alkylamido, C1-3dialkylamido, C1-8acylamino, C1-8alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl; aralkyl C1-4 wherein the aryl moiety is optionally substituted with hydroxy, halogen, nitro, alkoxy, cycloalkoxy or CF3, and wherein the alkyl moiety is optionally substituted with OH, halogen, alkoxy and cycloalkoxy; heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with C1-8alkyl OH, halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl, amido, C1-8alkylamido, C1-3dialkylamido, C1-8acylamino, C1-8alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl; heterocyclylalkyl (C1-C4) wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with C1-8alkyl, OH, halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl, amido, C1-8alkylamido, C1-3dialkylamido, C1-8acylamino, C1-8alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl or benzyl, and wherein said alkyl moiety is optionally substituted with OH, alkoxy, cycloalkoxy, halogen or haloalkyl; heteroaryl, which is optionally substituted with C1-4alkyl, halogen, nitro, CF3, alkoxy or cycloalkoxy; and heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with C1-4alkyl, halogen, nitro, CF3, alkoxy or cycloalkoxy.
In other preferred embodiments, R8 is selected from the group consisting of C1-8alkyl which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONF2, CO2H or xe2x95x90O; and C3-8cycloalkyl which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O.
In other preferred embodiments of the invention R3, R6a, R6b and R8 are selected from the group consisting of A and B,
wherein A is selected from the group consisting of
hydrogen;
C1-10alkyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H, xe2x95x90O and benzyloxy; said benzyloxy optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy and C3-12cycloalkoxy;
C2-10alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O;
C3-10cycloalkyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O;
C3-10cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O;
C3-12cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O,
aryl which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl and benzyl;
ar(C1-4)alkyl wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10alkylcarboxy, halogen, hydroxy, hydroxy(C1-10)alkoxy, nitro, trihalocarbon, benzyloxy, heterocyclyl, C1-10cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy and C3-12cycloalkoxy; said alkoxy and cycloalkoxy optionally substituted in one position at the alkyl moiety with hydroxy and said heterocyclyl is optionally substituted with C1-10alkyl; and wherein the alkyl moiety of said ar (C1-4)alkyl is optionally substituted with OH, halogen, C1-10alkoxy or C3-12cycloalkoxy said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino, C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl and benzyl;
heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino C1-10alkylsulfonylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl and benzyl, and wherein said alkyl moiety is optionally substituted with OH, C1-10alkoxy, C3-12cycloalkoxy, C3-12cycloalkyl, halogen and halo(C1-10)alkyl;
heteroaryl, which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, CF3, C1-10alkoxy, C3-12cycloalkoxy and oxo; and
heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, trihalocarbon, C1-10alkoxy and C3-12cycloalkoxy; and
B is selected from the group consisting of
C1-10alkyl which is unbranched or branched and is substituted with 1-3 substituents chosen from the group consisting of benzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl, pyridylmethoxy, thienylmethoxy and alkylamino; said substituents optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy and oxo; said substituted C1-10alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H, and xe2x95x90O
C2-10alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O;
C3-10cycloalkyl which is substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl and C3-12cycloalkyl; said substituted C3-10cycloalkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O;
C3-10cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy, halogen, halo(C1-10)alkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H and xe2x95x90O;
C3-12cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, halo(C1-10)alkyl, and xe2x95x90O said substituted C3-12cycloalkyl(C1-10)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkoxy, C3-12cycloalkoxy, xe2x95x90NOH, xe2x95x90NOCONH2, and CO2H;
aryl which is substituted with 1-3 substituents chosen from the group consisting of carbamyl, amido, C1-10alkylamido, C1-10dialkylamido, C1-10acylamino and C1-10alkylsulfonylamino; said substituted aryl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, Cxe2x95x90NOH, Cxe2x95x90NOCONH2, phenyl and benzyl;
ar(C1-4)alkyl wherein the aryl moiety is substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10alkylcarboxy, hydroxy(C1-10)alkoxy, nitro, benzyloxy, heterocyclyl, C1-10cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10alkoxy and C3-12cycloalkoxy; said alkoxy and cycloalkoxy substituted in one position at the alkyl moiety with hydroxy and said heterocyclyl is optionally substituted with C1-10alkyl and wherein the alkyl moiety of said ar (C1-4)alkyl is optionally substituted with OH, halogen, C1-10alkoxy and C3-12cycloalkoxy said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy; and said substituted ar(C1-4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of halogen, hydroxy, trihalocarbon, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy and C3-12cycloalkoxy
heterocyclyl which is substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of carbamyl, C1-10acylamino and C1-10alkylsulfonylamino; said substituted heterocyclyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, amido, C1-10alkylamido, C1-10dialkylamido, Cxe2x95x90NOH, Cxe2x95x90NOCONHR, phenyl and benzyl;
heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10acylamino, C1-10alkylsulfonylamino, and C1-10alkyl, said C1-10alkyl substituted with OH, C1-10alkoxy, C3-12cycloalkoxy, C3-12cycloalkyl, halogen or halo(C1-10)alkyl; said substituted heterocyclyl(C1-C4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, OH, halogen, C1-10alkoxy, C3-12cycloalkoxy, NH2, C1-10alkylamino, C1-10dialkylamino, amido, C1-10alkylamido and C1-10dialkylamido,
heteroaryl, which is substituted with oxo; said substituted heteroaryl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, nitro, CF3, C1-10alkoxy and C3-12cycloalkoxy; and
heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is substituted with nitro; said heteroaryl(C1-4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12cycloalkyl, halogen, trihalocarbon, C1-10alkoxy and C3-12cycloalkoxy; and
provided that at least one of R3, R6a, R6b and R8 is B.
In certain preferred embodiments, R3 is A and is ar(C1-4)alkyl, preferably benzyl, wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of halogen, nitro, C1-10alkoxy, C3-12cycloalkoxy or CF3, and wherein the alkyl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of OH, halogen, C1-10alkoxy and C3-12cycloalkoxy. When the ar(C1-4)alkyl is benzyl, said aryl moiety is preferably substituted with with cyclopentyloxy and methoxy.
In certain preferred embodiments, R6a is A and is hydrogen.
In certain preferred embodiments R6b is A and is selected from the group consisting of
hydrogen;
C1-8alkyl which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; and
C3-8cycloalkyl which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O.
In certain preferred embodiments R8 is B and is selected from the group consisting of
C1-10alkyl which is unbranched or branched and is substituted with 1-3 substituents chosen from the group consisting of benzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl, pyridylmethoxy, thienylmethoxy and alkylamino, said substituents optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy and oxo.
In certain preferred embodiments R3 is A and is ar(C1-4)alkyl, preferably benzyl, wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of halogen, nitro, C1-10alkoxy, C3-12cycloalkoxy or CF3, and wherein the alkyl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of OH, halogen, C1-10alkoxy and C3-12cycloalkoxy and when the ar(C1-4)alkyl is benzyl, said aryl moiety is preferably substituted with with cyclopentyloxy and methoxy; R6a is A and is hydrogen; R6b is A and is selected from the group consisting of hydrogen, C1-8alkyl which is unbranched or branched and is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; and C3-8cycloalkyl which is optionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, xe2x95x90NOH, xe2x95x90NOCONH2, CO2H or xe2x95x90O; and R8 is B and is selected from the group consisting of C1-10alkyl which is unbranched or branched and is substituted with 1-3 substituents chosen from the group consisting of benzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl, pyridylmethoxy, thienylmethoxy and alkylamino, said substituents optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkoxy and oxo.
Certain preferred adenine compounds according to the invention include: 6-ethylamino-3-hexyl-3H-purine; 3-hexyl-6-methylamino-3H-purine; 8-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H-purine; 8-cyclopropyl-3-ethyl-6-propylamino-3H-purine; 8-cyclopropyl-3-ethyl-6-methylamino-3H-purine; 3-butyl-6-ethylamino-3H-purine; 3-butyl-8-cyclopropyl-6-ethylamino-3H-purine; 6-ethylamino-3-propyl-3H-purine; 8-cyclopropyl-6-ethylamino-3-propyl-3H-purine; 8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine; 3-benzyl-6-ethylamino-3H-purine; 8-cyclopropyl-6-cyclopropylamino-3-propyl-3H-purine; 3-(2-methylbutyl)-6-(2-(piperazine-1-yl)ethylamino)-3H-purine; 3-cyclohexylmethyl-6-ethylamino-3H-purine; 3-benzyl-6-ethylamino-8-(1-methylethyl)-3H-purine; 3-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H-purine; 3-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine; 3-ethyl-8-isopropyl-6-benzylamino-3H-purine; 3-ethyl-8-isopropyl-6-ethylamino-3H-purine; 3-ethyl-8-cyclopentyl-6-benzylamino-3H-purine; 3-ethyl-8-cyclopentyl-6-ethylamino-3H-purine; 3-(4-chlorobenzyl)-6-ethylamino-3H-purine; 3-(2-chlorobenzyl)-6-ethylamino-3H-purine; 3-(2-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine; 6-benzylamino-8-cyclopropyl-3-propyl-3H-purine; 8-cyclopropyl-6-hexylamino-3-propyl-3H-purine; 8-cyclopropyl-3-propyl-6-(4-pyridylmethylamino)-3H-purine; 6-cyclopentylamino-8-cylopropyl-3-propyl-3H-purine; 6-butylamino-8-cyclopropyl-3-propyl-3H-purine; 8-cyclopropyl-6-(2-hydroxyethylamino)-3-propyl-3H-purine; 6-(3-cyclopentyloxy-4-methoxybenzylamino)-8-cyclopropyl-3-propyl-3H-purine; 6-amino-8-cyclopropyl-3-propyl-3H-purine; 3-ethyl-6-cyclopentylamino-8-isopropyl-3H-purine; 6-cyclohexylamino-8-isopropyl-3-propyl-3H-purine; 6-cyclopentylamino-8-isopropyl-3-propyl-3H-purine; 3-ethyl-6-cyclopentylamino-8-cyclopropyl-3H-purine; 3-(4-chlorobenzyl)-6-cyclopentylamino-8-cyclopropyl-3H-purine; 6-cyclopentylamino-3-(3-cyclopentyloxy-4-methoxybenzyl)-8-isopropyl-3H-purine; 3-(2-chlorobenzyl)-6-cyclopentylamino-8-isopropyl-3H-purine; 8-cyclopropyl-6-diethylamino-3-propyl-3H-purine hydrochloride; 8-cyclopropyl-6-(3-pentylamino)-3-propyl-3H-purine hydrochloride; 6-ethylamino-8-isopropyl-3-(4-pyridylmethyl)-3H-purine; 3-ethyl-8-isopropyl-6-ethylamino-3H-purine; 3-ethyl-8-cyclopentyl-6-benzylamino-3H-purine; 3-ethyl-8-cyclopentyl-6-ethylamino-3H-purine; 3-cylcohexylmethyl-6-ethylamino-3H-purine; 3-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H-purine; 8-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H-purine; 8-cyclopropyl-3-ethyl-6-propylamino-3H-purine; 8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine; 3-hexyl-6-methylamino-3H-purine; 3-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine; 3-ethyl-8-isopropyl-6-benzylamino-3H-purine; 3-butyl-6-ethylamino-3H-purine; 3-butyl-8-cyclopropyl-6-ethylamino-3H-purine; 8-cyclopropyl-6-ethylamino-3-propyl-3H-purine; 8-cyclopropyl-6-cyclopropylamino-3-propyl-3H-purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine; and 3-ethyl-6-ethylamino-8-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine.
Other preferred adenine compounds according to the invention include: 3,8-diethyl-6-morpholino-3H-purine; 3-ethyl-6-ethylamino-8-((3-cyclopentyloxy-4-hydroxy)benzyl)-3H-purine; 3-[3-(3-trimethylsilylethoxymethoxy)cyclopentyloxy-4-methoxy)benzyl)-6-ethylamino-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-(furan-2-yl-methoxy)-4-methoxy-benzyl]-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-(3-hydroxycyclopentyloxy)-4-methoxy-benzyl]-8-isopropyl-3H-purine; 6- Amino 3-[3-(3-hydroxycyclopentyloxy)-4-methoxy-benzyl]-8-isopropyl-3H-purine; 3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine; 6-Ethylamino-3-(3-butoxy-4-methoxy-benzyl)-8-isopropyl-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine; 6-ethylamino-2-(3,4-dimethoxybenzyl)-8-isopropyl-3H-purine; 6-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-3H-purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-dimethylamino-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-(3-hydroxycyclopentyloxy)-4-methoxybenzyl)]-8-(1-hydroxy-1-methylethyl)-3H-purine; 6-ethylamino-9-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-isopropyl-3H-purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-amino-8-isopropyl-3H-purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-(3-cyclopentyloxy-4-methoxybenzylamino)-8-isopropyl-3H-purine; 6-ethylamino-8-isopropyl-3-(4-methoxybenzyl)-3H-purine; 3-(3-((3-hydroxy)cyclopentyloxy)-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-(N-benzoyl-N-ethylamino)-8-isopropyl-3H-purine; 3-(4-chlorobenzyl)-6-cyclopropylamino-8-isopropyl-3H-purine; 6-ethylamino-8-isopropyl-3-[(4-methoxy-3-(4-hydroxybutoxy))benzyl]-3H-purine; 6-ethylamino-3-(4-fluorobenzyl)-8-isopropyl-3H-purine; 3-(3-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine 3-[3-(3-Hydroxy-cyclopentyloxy)-4-methoxy-benzyl]-8-(1-hydroxy-1-methyl-ethyl)-3H-purine; 3-[3-(3-hydroxy)cyclopentyloxy)]-4-methoxy)benzyl)-6-ethylamino-8-isopropyl-3H-purine; 6-amino-3-(3,4-dimethoxybenzyl)-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-cyclopentylmethoxy-4-methoxy-benzyl]-8-isopropyl-3H-purine; 6-ethylamino-3-(3-hydroxy-4-methoxybenzyl)-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-(2,2-dimethylaminoethoxy-4-methoxy)]-8-isopropyl-3H-purine; 3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-methyl-1-hydroxy)ethyl]-6-ethylamino-3H-purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-((2,2,2-trifluoroethyl)amino)-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-(2,2,2)-azabicyclooctan-3-yloxy)-4-methoxy]-8-isopropyl-3H-purine; 6-Ethylamino-3-[3-(1-methylpiperidin-4-yl-methoxy)-4-methoxy-benzy]-8-isopropyl-3H-purine; 6-amino-8-isopropyl-3-[(4-methoxy-3-([(4-hydroxybutoxy))benzyl]-3H-purine; 3-{2-(4-chlorophenyl)-ethyl]-6-ethylamino-8-isopropyl-3H-purine; 3-(4-chlorobenzyl)-6-((1-hydroxy)cyclopentylamino)-8-isopropyl-3H-purine; 3-(4-chlorobenzyl)-6-cyclopentylamino-8-isopropyl-3H-purine; 6-amino-3(3,4-methylenedioxybenzyl)-8-isopropyl-3H-purine; 6-Ethylamino-3-[(exo-8-methyl-8-azabicyclo(3,2,1)-octan-3-yl-oxy)-4-methoxy-benzy]-8-isopropyl-3-H-purine; 3-(4-chlorophenyl)-6-ethylamino-8-isopropyl-3H-purine; 6-ethylamino-3-[(3-hydroxy-4-methoxy)benzyl]-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine; 6-Ethylamino-3-[(3-pyridin-4-yl-methoxy)N-oxide-4-methoxy]-8-isopropyl-3H-purine; 3-[3-Cyclohexanyl-4-oxy-4-methoxy-benzyl]-6-ethylamino-8-isopropyl-3H-purine; 3-(4-chlorobenzyl)-2,6-di(ethylamino)-8-isopropyl-3H-purine; 6-amino-3-(3-hydroxy-4-methoxy)-benzyl)-8-isopropyl-3H-purine; 6-amino-3-[3-(4-hydroxybutoxy-4-methoxy)benzyl]-8-(1-hydroxy-1-methylethyl)-3H-purine; 6-amino-3-(4-chlorobenzyl)-8-isopropyl-3H-purine; 6-amino-3-cyclopentylmethyl-8-isopropyl-3H-purine; 8-cyclopropyl-3-ethyl-6-ethylamino-3H-purine; 6-Ethylamino-8-isopropyl-3-[3-(pyridin-4-yl-methoxy)-4-methoxy-benzyl]-3H-purine; 6-Ethylamino-3-(1-oxopyridin-4-yl-methyl)-8-isopropyl-3H-purine, and 6-amino-3-[(3-hydroxy-4-methoxy)benzyl)]]-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine, 3-(3-COOmethyl-4-methoxbenzyl)-6-ethylamino-8-isopropyl-3H-purine, 3-(3-piperadine-4-methoxbenzyl)-6-ethylamino-8-isopropyl-3H-purine; 3-(3-COOH-4-methoxbenzyl)-6-ethylamino-8-isopropyl-3H-purine, 3-(3-pyrrole-benzyl)-6-ethylamino-8-isopropyl-3H-purine, 3-butyl-6-pentylamino-8-cyclopropyl-3H-purine, 3-butyl-6-cyclopentylamino-8-cyclopropyl-3H-purine, 3-butyl-6-dimethylamino-8-cyclopropyl-3H-purine and their pharmaceuticaly acceptable salts.
In other preferred embodiments, the adenine compound is selected from the group consisting of 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2-methoxy)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-methoxy)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3,4-dimethoxy)benzyl]-8-[(1-(4-methyl)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(4-chloro)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine; 6-(3-fluoro)benzyloxyamino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,5-dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4-dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3,4-methylenedioxybenzyloxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(2-thienylmethoxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3-thienylmethoxy-1-methyl)ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(1-oxo-octyl)amino-1-methyl)ethyl]-3H-purine; 6-amino-3-(3,4-methylenedioxybenzyl)-8-[(1-(4-fluorobenzyloxy)-1-methyl-ethyl]-3H-purine; 6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[1-(4-pyridylmethoxy)-methyl-ethyl]-3H-purine; 6-ethylamino-3-(3-benzyloxy-4-methoxybenzyl)-8-isopropyl-3H-purine; 3-[(3-benzyloxy-4-methoxy)benzyl-8-[(1-benyloxy-1-methyl)-ethyl]-6-ethylamino-3H-purine; 6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-[1-(4-methoxybenzyloxy)-1-methyl-ethyl]-3H-purine; 6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-methylethenyl)-3H-purine; 6-Amino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine; 6-amino-8-[(1-benzyloxy-1-methyl)ethyl]-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-3H-purine; 6-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methyl-ethyl]-3H-purine; [8-(1-benzyloxy-1-methyl)ethyl]3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-3H-purine; 6-ethylamino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine; 6-ethylamino-3-(3-,4-methylenedioxybenzyl)-8-isopropyl-3H-purine; 3-(3-benzyloxy-4-methoxy-benzyl)-6-ethylamino-8-isopropyl-3H-purine; 6-Amino-3-(3,4-dimethoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methylethyl]-3H-purine; 6-(amino-8-(1-benzyloxy-1-methylethyl)-3-(3,4-dimethoxybenzyl)-3H-purine; 6-amino-3-[(3-benzyloxy-4-methoxy)benzyl]-8-[(1-benzyloxy-1-methyl)ethyl]-3H-purine; 6-Amino-3-(3,4-dimethyoxybenzyl)-8-(1-methylethenyl)-3H-purine 6-amino-3-((3-benzyloxy-4-methoxy)-bezyl)-8-isopropyl-3H-purine; 3-(3-benzyloxy-4-nitro-benzyl)-6-ethylamino-8-isopropyl-3H-purine; 3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-(1-methyl-ethenyl)-3H-purine and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the adenine compound is selected from 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-3H-purine (PDE IV I50=2.15 xcexcM); 3-(4-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine (PDE IV I50=1.13 xcexcM); 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (PDE IV I50=0.32 xcexcM); and (particularly preferred) 6-cyclopentyl-8-cyclopropyl-3-propyl-3H-purine (PDE IV I50=0.03 xcexcM); and their pharmaceutically acceptable salts.
The present invention is also related to isoguanine compounds which are precursors of the adenine compounds described above. In addition to their role as precursor compounds, it has been surprisingly discovered that these compounds also have significant PDE IV inhibitory activity.
The present invention therefore is directed in part to a compound of the formula (II) 
wherein
R2 is O or S; and R3, R6a, R6b and R8 are the same or different and are represent the same groups as those set forth with respect to compound (I) above.
Preferred isoguanine compounds according to the present invention include 6-cyclopentyamino-8-cyclopropyl-3,7-dihydro-3-propyl-2-thio-2H-purin-2-one (PDE IV I50=7.41 xcexcM); 8-cyclopropyl-3,7-dihydro-6-(2-hydroxythylamino)-2-thio-2H-purin-2-one (PDE IV I50=4.48 xcexcM); (particularly preferred) 8-cyclopropyl-3,7-dihydro-6-(4-pyridylmethylamino)-2-thio-2H-purin-2-one (PDE IV I50=0.41 xcexcM); and their pharmaceutically acceptable salts.
The present invention is also related to 2,6-dithioxanthine compounds which are precursors of the adenine compounds described above. In addition to their role as precursor compounds, it has been surprisingly discovered that these compounds also have significant PDE IV inhibitory activity.
The present invention therefore is directed in part to a compound of the formula (III) 
wherein
R3 and R8 are the same or different and are represent the same groups as those set forth with respect to compound (I) above.
Preferred dithioxanthine compounds according to the present invention include 3-benzyl-3,7-dihydro-8-(1-methylethyl)-2,6-dithio-1H-purin-2,6-dione (PDE IV I150=3.40 xcexcM); 3.03 xcexcM); 3-(4-chlorobenzyl)-8-isopropyl-3,7-dihydro-2,6-dithio-3,7-purin-2,6-dione (PDE dione (PDE IV I50=2.27 xcexcM); 3-(3-cyclopentyloxy-4-methoxybenzyl)-3,7-dihydro-8-isopropyl-2,6-dithio-1H-purin-2,6-dione (PDE IV I50=0.80 xcexcM); (particularly preferred) 8-cyclopropyl-3,7-dihydro-1,3-diethyl-2,6-dithio-1H-purin-2,6-dione (PDE IV I50=0.42 xcexcM); and their pharmaceutically acceptable salts.
As used herein, the following terms are intended to have the meaning as understood by persons of ordinary skill in the art, and are specifically intended to include the meanings set forth below:
As used herein, the term xe2x80x9calkylxe2x80x9d means a linear or branched saturated aliphatic hydrocarbon group having a single radical and 1-10 carbon atoms. Examples of alkyl groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branched alkyl means that one or more alkyl groups such as methyl, ethyl or propyl, replace one or both hydrogens in a xe2x80x94CH2xe2x80x94 group of a linear alkyl chain.
The term xe2x80x9ccycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic hydrocarbon ring system having a single radical and 3-12 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. Exemplary multicylic cycloalkyl rings include adamantyl and norbornyl.
The term xe2x80x9calkenylxe2x80x9d means a linear or branched aliphatic hydrocarbon group containing a carbonxe2x80x94carbon double bond having a single radical and 2-10 carbon atoms. A xe2x80x9cbranchedxe2x80x9d alkenyl means that one or more alkyl groups such as methyl, ethyl or propyl replace one or both hydrogens in a xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90 linear alkenyl chain. Exemplary alkenyl groups include ethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.
The term xe2x80x9ccycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbonxe2x80x94carbon double bond having a single radical and 3 to 12 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenyl ring is norbornenyl.
The term xe2x80x9ccycloaklylalkylxe2x80x9d or xe2x80x9ccycloalkyl-alkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system, wherein the ring is substituted with an alkyl group, as defined above to include a linear or branched aliphatic hydrocarbon group having a single radical
The term xe2x80x9carylxe2x80x9d means a carbocyclic aromatic ring system containing one, two or three rings which may be attached together in a pendent manner or fused, and containing a single radical. Exemplary aryl groups include phenyl and naphthyl.
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d or xe2x80x9caryl-alkylxe2x80x9d means an alkyl group as defined above to include a linear or branched saturated aliphatic hydrocarbon group having a single radical, wherein the alkyl is substituted with an aryl group, as defined above to include a carbocyclic aromatic ring system containing one, two or three rings which may be attached together in a pendent manner or fused, and containing a single radical.
The term xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d means cyclic compounds having one or more heteroatoms (atoms other than carbon) in the ring, and having a single radical. The ring may be saturated, partially saturated and unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, and dihydrofuran.
The term xe2x80x9cheteroarylxe2x80x9d means unsaturated heterocyclic radicals, wherein heterocyclic is as previously described. Exemplary heteroaryl groups include unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, and pyrazinyl, unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, quinolyl, isoquinolyl; unsaturated 3 to 6 membered heteromonocyclic groups containing an oxygen atom, such as furyl; unsaturated 3 to 6 membered heteromonocyclic groups containing a sulfur atom, such as thienyl; unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl; unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term xe2x80x9cheteroarylxe2x80x9d also includes unsaturated heterocyclic radicals, wherein heterocyclic is as previously described, in which the heterocyclic group is fused with an aryl group, in which aryl is as previously described. Exemplary fused radicals include benzofuran, benzdioxole and benzothiophene.
The term xe2x80x9cheterocyclylalkylxe2x80x9d means heterocyclic groups, as defined above to include compounds having one or more heteroatoms (atoms other than carbon) in the ring, and having a single radical, wherein the ring may be saturated, partially saturated and unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen, in which the heterocyclic group is substituted with an alkyl group, as defined above to include linear or branched saturated aliphatic hydrocarbon group having a single radical. Exemplary heterocyclylalkyl groups include pyrrolidinyl-methyl, imidazolidinyl-methyl, piperidino-methyl, piperazinyl-methyl, morpholinyl-methyl, and thiazolidinyl-methyl.
The term xe2x80x9cheteroaralkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d means heteroaryl radicals, wherein heteroaryl is as previously described, wherein the heteroaryl group is substituted with an alkyl group as defined above to include linear or branched saturated aliphatic hydrocarbon groups having a single radical. Exemplary heteroaralkyl groups include pyrrolyl-methyl, pyridyl-methyl, pyrimidyl-methyl, pyrazinyl-methyl, indolyl-methyl, quinolyl-methyl, isoquinolyl-methyl, furyl-methyl, thienyl-methyl, oxazolyl-methyl, benzoxazolyl-methyl, thiazolyl-methyl, benzothiazolyl-methyl, benzofuran-methyl and benzothiophene-methyl.
The term xe2x80x9cacylxe2x80x9d means an Hxe2x80x94C(O)- or alkyl-C(O)-group in which the alkyl group is as previously described. Exemplary acyl groups include formyl, acetyl, propanoyl, and 2-methylpropanoyl.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl-O-group in which the alkyl group is as previously defined, to include a linear or branched saturated aliphatic hydrocarbon group having a single radical. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, and n-butoxy. The term xe2x80x9ccycloalkoxyxe2x80x9d means a cycloalkyl-O-group in which the cycloalkyl group is as previously defined, to include non-aromatic mono- or multicyclic hydrocarbon ring systems having a single radical. Exemplary cycloalkoxy groups include cyclopentyloxy.
The term xe2x80x9camidoxe2x80x9d or xe2x80x9caminocarbonylxe2x80x9d means xe2x80x94C(O)NH2.
The term xe2x80x9caminoxe2x80x9d means the group xe2x80x94NH2xe2x80x94. The term xe2x80x9calkylaminoxe2x80x9d means an amino group which has been substituted with an alkyl group as defined above, and the term dialkylamino means an amino group which has been substituted with two alkyl groups, as defined above. The term xe2x80x9cacylaminoxe2x80x9d means an amino group which has been substituted with an acyl group as defined above.
The term xe2x80x9ccarbamylxe2x80x9d is the group CH2NO.
The term xe2x80x9csulfonylxe2x80x9d means the divalent radical SO2. The term xe2x80x9calkylsulfonylaminoxe2x80x9d means a sulfonyl group which is substituted with an amino group as defined above, and an alkyl group as defined above.
As used herein, the term xe2x80x9cpatientxe2x80x9d includes both human and other mammals.
The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed compounds. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, secium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.
The invention disclosed herein is also meant to encompass all prodrugs of the disclosed compounds. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug in vivo.
The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the urine, blood or other biological samples.
The invention disclosed herein is also meant to encompass the disclosed compounds being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
As used herein, the term xe2x80x9cstereoisomersxe2x80x9d is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached.
The term xe2x80x9cenantiomerxe2x80x9d or xe2x80x9cenantiomericxe2x80x9d refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
The term xe2x80x9cracemicxe2x80x9d refers to a mixture of equal parts of enantiomers and which is optically inactive.
The term xe2x80x9cresolutionxe2x80x9d refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
The compounds of the present invention can be administered to anyone requiring PDE IV inhibition. Administration may be orally, topically, by suppository, inhalation or insufflation, or parenterally.
The present invention also encompasses all pharmaceutically acceptable salts of the foregoing compounds. One skilled in the art will recognize that acid addition salts of the presently claimed compounds may be prepared by reaction of the compounds with the appropriate acid via a variety of known methods.
Various oral dosage forms can be used, including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders and liquid forms such as emulsions, solution and suspensions. The compounds of the present invention can be administered alone or can be combined with various pharmaceutically acceptable carriers and excipients known to those skilled in the art, including but not limited to diluents, suspending agents, solubilizers, binders, disintegrants, preservatives, coloring agents, lubricants and the like.
When the compounds of the present invention are incorporated into oral tablets, such tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, multiply compressed or multiply layered. Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents. When the compounds of the present invention are to be injected parenterally, they may be, e.g., in the form of an isotonic sterile solution. Alternatively, when the compounds of the present invention are to be inhaled, they may be formulated into a dry aerosol or may be formulated into an aqueous or partially aqueous solution.
In addition, when the compounds of the present invention are incorporated into oral dosage forms, it is contemplated that such dosage forms may provide an immediate release of the compound in the gastrointestinal tract, or alternatively may provide a controlled and/or sustained release through the gastrointestinal tract. A wide variety of controlled and/or sustained release formulations are well known to those skilled in the art, and are contemplated for use in connection with the formulations of the present invention. The controlled and/or sustained release may be provided by, e.g., a coating on the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained release matrix.
Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms, are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) 2nd edition, published by Marcel Dekker, Inc., incorporated by reference herein. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington""s Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference. Techniques and composition for making liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger and Banker, editors) published by Marcel Dekker, Inc., incorporated herein by reference.
When the compounds of the present invention are incorporated for parenteral administration by injection (e.g., continuous infusion or bolus injection), the formulation for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and such formulations may further comprise pharmaceutically necessary additives such as stabilizing agents, suspending agents, dispersing agents, and the like. The compounds of the invention may also be in the form of a powder for reconstitution as an injectable formulation.
The dose of the compounds of the present invention is dependent upon the affliction to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleterious side-effects, and the particular compound utilized, among other things.